As a pharmaceutical composition comprising a dual antagonist against PGD2/TXA2 receptors, a compound of the formula:
wherein RX is optionally substituted single ring or fused heterocyclyl; X is hydrogen or alkyl, was described in WO 99/15502. The above mentioned compound has a substituent of the formula: —CH2—CH═CH—CH2—CH2—CH2—COOX wherein X is hydrogen or alkyl, as an α chain and R on an ω chain is a single or fused heterocycl optionally substituted with amino, halogen, hydroxy and the like.
Further, the other compounds having a [2.2.1] bicyclo skeleton similar to the compounds of the present invention have been described in WO97/00853 and the like. In this publication, it is described that the compounds are useful as prostagrandin D2 (PGD2) antagonists.
However, in these publications, almost none of compound having other substituents than those represented by the formula:
wherein X1 and X3 are each independently optionally substituted aryl, optionally substituted heteroaryl or optionally substituted non-aromatic heterocyclyl; X2 is a bond, —CH2—, —S—, —SO2— and the like; X4 is —CH2— and the like; m is 0 or 1; p is 0 or 1 as the ω chain, and furthermore, the formula: —CH2—CH═CH—CH2—CH2—CH2—COOR2 wherein R2 is hydrogen or alkyl, as the α chain of bicyclic ring, has been described.
PGD2 receptor antagonists have a quite different character from that of TXA2 receptor antagonists in the site and mechanism of action and indications thereof.
On the other hand, a compound having a dual antagonistic activity against both a TXA2 receptor and a PGD2 receptor can be useful as therapeutic agents for various diseases caused by TXA2 or PGD2.
For example, in the case of bronchial asthma, it is known that TXA2 cause potent tracheal contraction and respiratory anaphylaxis and PGD2 effects infiltration of eosionophils. From these comprehension, TXA2 and PGD2 are thought to be one of causative substances of the pathopoiesis and advance of asthma, thus the dual antagonistic compounds are expected to be more potent agents for treating asthma than ever known antagonists.
Further, in the case of allergic rhinitis, it is recognized that TXA2 and PGD2 cause the swelling of nasal mucosa through the aggravation of vascular permeability, and PGD2 induces the nasal blockage through the enlargement of vascular volume. Therefore, the dual antagonistic compounds are expected to be more potent agents for treating nasal blockage than ever known antagonists.
These diseases and condition thereof might be treated by administering both a TXA2 receptor antagonist and a PGD2 receptor antagonist at the same time, for example, in combination therapy or as a mixture thereof. But the administration of two or more agents often causes some problems due to the difference of their metabolic rate. For example, when the antagonists are different from each other in the time to reach a maximum blood concentration or the duration of action, they do not always efficiently exhibit each receptor antagonistic effect at the same time, failing to give a desired additive or synergic effect.
It has therefore been desired to develop medicines having a dual antagonistic activity against TXA2/PGD2 receptors, which exhibit new excellent therapeutic effects and can be used for many indications.
On the other hand, it was disclosed that 3-oxa-derivatives were prepared as metabolically stable TXA2/PGH2 receptor antagonists in Bioorganic & Medicinal Chemistry Letters, Vol.2, No.9, pp. 1069–1072, 1992. The active value of the compound was only described but the metabolic stability has not been described in the literature.
wherein, Z is p-fluorophenyl; Rω is benzenesulfonamino and the like.
Furthermore, it was reported in PROSTAGLANDINS, 1986, 31, 95 that ILOPROST, PGI2 mimetics was stabilized metabolically by converting to the 3-oxa-derivative. But, remaining activity of each compound was only compared under a presence of the metabolic enzyme of a rat and the metabolic stability did not mentioned, since there was a possibility of a production of active metabolites